Disorders of pregnancy pose a major public health problem because they involve approximately 10% of human pregnancies. Preeclampsia (PE) is one such disorder which presents itself with maternal symptoms of global endothelial disease, including glomeruloendotheliosis, liver and cerebral vascularitis. Diagnostic symptoms are high blood pressure (>140), proteinuria (>0.3 gm/ml) and general edema. (ACOG Committee on Obstetric Practice, 2002) PE is a pregnancy-specific systemic disorder characterized by a cascade of events and symptoms, including impaired trophoblast invasion, decreased placental perfusion, placental ischemia, oxidative stress and imbalance in angiogenic and prothrombotic factors which can lead to apoptosis of trophoblasts(20-23). Studies have also shown that in preeclampsia, there are elevated levels of circulating or placental TNFα, IL-6, IL-8. IFNγ, leptin, perturbed renin angiotensin system, complement split products, antibodies to phospholipids, sFlt-1, soluble endoglin, IL2, decreased IL10, NO, hypoxia(18, 24-31) amongst host of other factors. Uteroplacental abnormalities can result in shallow placentation, poor spiral artery remodeling, and placental ischemia. PE is strictly a placental condition; it resolves after delivery. PE is diagnosed in the later half of pregnancy and the relatively late onset of clinical signs and a complex pathobiology of PE present obstacles for its study. There exist no concrete in vitro or animal models that mirror the morphological and mechanistic underpinnings of PE.
Gestational diabetes, intrauterine growth restriction, and placental abruption are other pregnancy disorders associated with placental angiogenic anomalies and ischemia. Gestational diabetes is characterized by high blood glucose levels during pregnancy. About 3%-5% of all pregnant women in the U.S. are diagnosed with the condition, which is believed to result from hormonal changes that occur during pregnancy. Increases in hormone levels made in the placenta cause insulin resistance, which increases as the placenta grows larger and produces more hormones. If the pancreas cannot produce enough insulin to overcome the effect of the increased hormones during pregnancy, sugar levels will rise, resulting in gestational diabetes.
Placental abruption affects about 9 in 1,000 pregnancies. It can occur any time after the 20th week and results from a cascade of pathophysiologic processes ultimately leading to the separation of the placenta prior to delivery. Pregnancies complicated by abruption result in increased frequency of low birth weight, preterm delivery, stillbirth, and perinatal death.(32) The causes are not well-understood; some women develop it without any identifiable cause. Known risk factors high blood pressure (140/90 mm Hg or higher), either chronic or caused by the pregnancy (either by pregnancy-induced hypertension or preeclampsia).
Intrauterine growth retardation (IUGR), defined as less than 10 percent of predicted fetal weight for gestational age, may result in significant fetal morbidity and mortality if not properly diagnosed. The condition is most commonly caused by inadequate maternal-fetal circulation, with a resultant decrease in fetal growth. Maternal causes of IUGR account for most uteroplacental cases. Chronic hypertension is the most common. Moreover, the infants of hypertensive mothers have a three-fold increase in perinatal mortality compared with infants with IUGR who are born of normotensive mothers. IURR also result from preeclampsia, which causes placental damage that result in uteroplacental insufficiency due to luminal narrowing and medial degeneration, leading to diminished blood flow to the developing infant. Consequently, the infants fail to grow normally. Treatment of the mother and the growth-restricted fetus is typically dictated by the etiology of the condition. Maternal hyperoxygenation has been evaluated in several studies and low-dose aspirin (150 mg per day) has also been studied.
Efforts have been made to provide assays for the diagnosis of PE. Numerous assays employ identification and/or measurement of various biochemical markers such as specific protein or nucleic acids in maternal samples. Exemplary are U.S. Pat. Nos. 6,735,529; 6,620,590; 6,495,330; and 6,258,540 and United States Patent Publication Nos. 2007/0185200; 2004/0038305; 2007/01785302007/0104707; 2007/0020766; and 2006/0183175. None appear to work with any consistent, reliable, degree of success. Another known assay involves culturing human trophoblasts in the presence or absence of a pregnant woman's serum or plasma and comparing viability of the cells cultured. See United States Patent Publication No. 2005/0074746. Like the biochemical marker assays, this cell-based assay is reported to be an inconsistent and unreliable predictive measure for PE.
Efforts also have been made to provide mouse strains exhibit phenotypes associated with various adverse pregnancy outcomes, including PE. Hayakawa et al. demonstrated high fetal resorption rates, hypertension, proteinuria and glomerular nephritis in pregnant BALB/C mice exposed to IL-12 stimulated splenocytes(14). Takimoto et al. mated transgenic mice expressing components of the human renin-angiotensin system, resulting in the development of PE manifestations(15). Similarly, mice deficient in the cyclin-dependent kinase inhibitor p57kip1 exhibit some of the features associated with PE (16). Proteinuria, hypertension, glomerulosclerosis and small liter size were also noted in spontaneously hypertensive (BPH/5) matings(17). However, these models do not address the issue of intrinsic response in wild type animals to circulating inflammatory components and placenta-derived factors.